In the first two years of this project we have demonstrated that women with a history of gestational diabetes mellitus (GDM), who are at high risk for developing non-insulin dependent diabetes mellitus (NIDDM), show impaired glucose tolerance, blunted glucose-stimulated insulin release and increased glycemic reactivity to adrenergic stimulation, compared to controls. The overall aim of this project is to determine if glucose tolerance and glucose-stimulated insulin release in women who have had GDM can be improved and/or corrected by alpha adrenergic blockade. We will evaluate the effects of phenoxybenzamine (a broad spectrum alpha blocker) on glucose and insulin responses to an oral glucose load, and insulin and glucose responses to an intravenous glucose stimulus, in a cohort of women who have had GDM and are now euglycemic and in a group of normal parous women matched for age and weight. We predict that alpha adrenergic blockade will normalize the glucose and insulin responses of women with a history of GDM, but have no effect on controls. Such a result will confirm the hypothesis that the autonomic nervous system is involved in the pathophysiology of NIDDM. Furthermore, it would suggest that chronic alpha adrenergic blockade aimed at correcting this defect before NIDDM develops might be useful as a prophylaxis for the disease in at least one high risk group. If our hypothesis is confirmed, we would be poised to conduct a chronic prevention trial of alpha blockade in a larger number of subjects.